1,2-Dichloroethane → Bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate

HRID 1910506Notes

Reaction equation

HRID 1910506 reaction equation
Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)O)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2

Participants

9

Reactant 6

HCID 111,2-Dichloroethane3×HCID 757711-Hydroxybenzotriazole2×HCID 81531Diisopropylethylamine3×HCID 1230494,4'-Difluorobenzhydryl alcoholHCID 516892Sodium BicarbonateHCID 126734361-Azabicyclo(2.2.2)octane-3-carboxylic acid hydrochloride3×

Product 1

HCID 70925939Bis(4-fluorophenyl)methyl quinuclidine-3-carboxylateYield 31.7%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

Quinuclidine-3-carboxylic acid hydrochloride (96 mg, 0.50 mmol), EDC (131 mg, 0.68 mmol), and HOBT (104 mg, 0.68 mmol) were suspended in dry DMF (5 ml). Bis(4-fluorophenyl)methanol (100 mg, 0.45 mmol) and DIPEA (278 μl, 1.59 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Then, quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), HOBT (34.8 mg, 0.23 mmol), and DIPEA (79 μl, 0.45 mmol) were added again and stirring was continued for 4 days. Finally quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), and DIPEA (79 μl, 0.45 mmol) were added, and the suspension was stirred for additional 24 hours. The reaction was portioned between sat. NaHCO3 and Et2O, and the organic layer was separated, washed again with sat. NaHCO3 and then brine. The organic phase was dried over Na2SO4, filtered, and evaporated to afford bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate (51 mg, racemic mixture). The compound was used as such in the next step.

Workup

  1. stirringstirring
  2. waitwas continued for 4 days
  3. stirringthe suspension was stirred for additional 24 hours
  4. customthe organic layer was separated
  5. washwashed again with sat. NaHCO3
  6. dry with materialThe organic phase was dried over Na2SO4
  7. filtrationfiltered
  8. customevaporated

Sources & evidence

ORD record
ord-b2193eaa529447968246abbdf8cb4ad7
Source dataset
uspto-grants-2013_12
Patent number
US08604015B2

Reaction notes

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